Referred scheduling proposal

An application was submitted to include Vitamin D in Appendix H in the Poisons Standard.

Scheduling application

This is a general application. The applicant's proposed amendments to the Poisons Standard are as follows:

Appendix H - New Entry

Vitamin D.

The applicant's reasons for the request are:

Since August 2015, a high-dose (colecalciferol 7000 IU (175 micrograms)) vitamin D has been available as a Schedule 3 medicine with a dose of one capsule per week. Adherence to vitamin D supplementation is low and adherence is an important aspect of a therapeutic regimen for osteoporosis. Meta-analysis has demonstrated that weekly dosing doubles the odds of medication adherence compared to daily dosing (low dose vitamin D).

The uptake of weekly dose products is low and the reason appears to be that most consumers purchase the unscheduled daily dose vitamin D products via the checkout in pharmacies or supermarkets, both well beyond the range of influence of pharmacists. The result is that while pharmacists may be aware of the compliance benefits of once weekly vitamin D, they would only have limited opportunity of discussing this with consumers.

The ability to advertise the weekly product would prompt consumers to ask the pharmacist about its availability and appropriateness. Increased uptake would improve patient compliance, the ability to coordinate with weekly dose regimes of related medicines (e.g. bisphosphonates) and increased convenience for consumers.

A position statement commissioned by the Australia and New Zealand Bone and Mineral Society and Osteoporosis Australia reported that an estimated 31% of adults in Australia have inadequate vitamin D status (serum 25-OHD level <50 nmol/L) increasing to more than 50% in women during winter-spring and in people residing in Southern states (Nowson, C.A., et al., Vitamin D and health in adults in Australia and New Zealand: a position statement. Med J Aust, 2012. 196).

Australian studies have shown that the majority of aged care residents (55-85%) have vitamin D deficiency (Nowson, C.A., et al., Vitamin D in Australia: Issues and recommendations. Australian Family Physician, 2004. 33: p.133-138). Other people at high risk of vitamin D deficiency include people with limited sun exposure (e.g. those with skin conditions where avoidance of sunlight is advised, people who are institutionalised, those with dark skin, particularly if veiled), the obese and patients with malabsorption or on certain medications (e.g. anti-epileptic medications) that increase the excretion of vitamin D.

Current scheduling status

Vitamin D is currently listed in Schedule 3 and Schedule 4 of the SUSMP as follows:

Schedule 4

VITAMIN D for human internal therapeutic use except:

in preparations containing 25 micrograms or less of vitamin D per recommended daily dose; or

when included in Schedule 3.

Schedule 3

VITAMIN D for human therapeutic use in preparations containing 175 micrograms or less of vitamin D per recommended single weekly dose except in preparations containing 25 micrograms or less of vitamin D per recommended daily dose.

Index

VITAMIN D
cross reference: COLECALCIFEROL, ERGOCALCIFEROL

Schedule 4
Schedule 3

Relevant scheduling history

In October 2012, the ACMS considered a proposal by the same applicant to create a new Schedule 3 entry for vitamin D to allow a weekly dose up to 175 micrograms per recommended dose and to include vitamin D in Appendix H. The ACMS supported the proposal to allow the higher weekly dose, but advised against an Appendix H entry. Some members supported the Appendix H entry, stating that it would promote awareness of the weekly dosage regime. Other members did not support the Appendix H entry as public health activities were considered sufficient to promote appropriate use of vitamin D. There were also concerns about off label use and no limits on pack sizes. The committee also noted that other vitamin D products, as different formulations, were unscheduled and could be advertised. The delegate made a final decision (8 February 2013) to include vitamin D, as a single weekly dose of up to 175 micrograms (7000 IU), in Schedule 3 and not to include vitamin D in Appendix H.

Substance summary

The major natural source of vitamin D in humans comes from the action of ultraviolet light on 7 dehydrocholesterol in the skin to form provitamin D3 which is then converted to colecalciferol.

Figure 3.1: Structures of colecalciferol (A) and ergocalciferol (B)

Table 3.1: General information for Vitamin D

Property

Colecalciferol (vitamin D3)

Ergocalciferol (vitamin D2)

INN/BAN/AAN

colecalciferol

ergocalciferol

CAS No.

67-97-0

50-14-6

Chemical name

(5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3β-ol

(5Z,7E,22E)-9,10-secoergosta-5,7,10(19),22-tetraen-3β-ol

Molecular formula

C27H44O

C28H44O

Units

25 micrograms = 1000 IU

175 micrograms = 7000 IU

-

Molecular Weight

384.6

396.7

Pre-meeting public submissions

Four (4) public submissions were received and all supported the proposal. The main points were:

Low vitamin D can be corrected with appropriate supplementation. It commonly takes 2-3 months to restore optimal vitamin D levels. A minimum serum level of 50 nmol/L is recommended at the end of winter or in early spring (when levels are the lowest). Currently most vitamin D supplements are daily tablets with 1000 IU/tablet. The availability of an equivalent weekly dose is additional choice and potential benefit for consumers needing vitamin D supplementation. It can also assist in compliance, particularly for patients requiring supplementation over long periods.

Toxicity related to vitamin D is generally restricted to large doses, far in excess of the dose available in a weekly tablet (equivalent to 7 daily 1000 IU tablets).

Presumes that the proposal relates to Schedule 3 Vitamin D, once-a-week products (7000 IU) that currently cannot be advertised, since Vitamin D once daily products (1000 IU) listed as complementary medicines may be advertised. Assumes the usual advertising rules and regulations will apply and that it would not be likely that off-label use could be inadvertently promoted as a consequence of an Appendix H listing.

The benefits of a simplified dosing schedule, improved adherence to treatment, known safety profile and low toxicity all support appropriate advertising of the high strength products.

Permitting advertising of high strength Vitamin D supplements would lead to greater awareness of treatment options for a highly prevalent condition.

There is minimal chance that the product would be inadvertently promoted when safeguards exist such as packaging, pharmacist intervention, and current regulations and advertising approvals.

The benefits of advertising and raising awareness of Vitamin D to the undiagnosed and untreated community far outweigh any potential risks and are in the public health interest. Low vitamin D levels is a public health issue and relevant to certain groups of the Australian population.

Potential off-label use leading to adverse clinical outcomes would be minimal as pharmacist intervention and advice is likely to enhance adherence and minimise incorrect dosing. If a consumer did inadvertently take a daily dose of the 175 µg product, the risk of toxicity is minimal. Although there may be a risk that some consumers would initiate self-medication as a result of seeing a branded advertisement, lower dose vitamin D products are already readily available to consumers and any request for the higher dose Schedule 3 product would be handled through pharmacist intervention.

One of the submissions gave conditional support to the proposal, supporting the proposal on the condition that any advertising highlights a mandatory role of pharmacists in determining suitability for consumers. The main points were:

All advertisements must comply with the requirements specific to vitamins, as outlined in the Therapeutic Goods Advertising Code.

The inclusion of vitamin D on Appendix H has the potential to increase consumer awareness about vitamin D medicines that may improve medicine adherence and encourage discussions with health professionals.

The risk of inappropriate use or over consumption are small and are further reduced through the mandatory oversight of a pharmacist assessing therapeutic need and the labelling on the medicines.

Summary of ACMS advice to the delegate

The committee advised that Vitamin D be entered in Appendix H of the Poisons Standard.

The committee also recommended an implementation date of 1 June 2017.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: a) the risks and benefits of the use of a substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of a substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; f) any other matters that the Secretary considers necessary to protect the public health.

The reasons for the advice comprised the following:

Access for high-risk consumers to a once-weekly dose of Vitamin D from a pharmacist for effective ongoing supplementation is likely to be beneficial and safe. The compliance benefits, low-risk nature of the product and safeguards inherent in Schedule 3 mean the benefits of advertising the availability of this product exceed any potential risks.

Some of the risks to an Appendix H entry include: inter-individual tolerance to vitamin D varies considerably and infants and children are more susceptible, according to the approved PI. Inadvertent or deliberate misuse resulting in excessive dosing of vitamin D is also possible. Excessive intake of vitamin D can lead to development of hypercalcaemia and associated effects of hypercalciuria, ectopic calcification, renal and cardiovascular damage. Other symptoms of overdose are listed in the PI and CMI and may include anorexia, lassitude, nausea, vomiting, bone pain, weight loss and other effects.

Vitamin D is relatively safe and it is difficult to overdose on a Schedule 3 preparation, particularly if given under medical supervision through a pharmacist. The benefits include that some consumers find convenience in the Schedule 3 once-a-week dosage regime. This may lead to improved adherence to supplementation, particularly for long term regular treatment, and may be beneficial particularly for those with more severe deficiency or at higher risk (e.g. aged care residents, those with limited sun exposure, obese people and those with malabsorption conditions).

Weekly dose Vitamin D [contains 7000 IU (equiv. to 175 micrograms) colecalciferol per capsule] is indicated for: (a) treatment of vitamin D deficiency in adults or adolescents as directed by a medical practitioner or pharmacist and (b) prevention of vitamin D deficiency in high risk individuals under the supervision of a medical practitioner or pharmacist.

Vitamin D has low toxicity, is safe and is very difficult to overdose. The chance of significant toxicity from inclusion in Schedule H is low, particularly as large doses of Vitamin D (50,000 150,000 IU) are given under medical supervision without toxicity issues. In the event that the one-a-week formulation is taken as a daily dose (in error), the potential for toxicity is low. However, there are risks with excessive intake (see above).

Dosage is as per the Schedule 3 listing [one capsule (7000 IU / 175 micrograms colecalciferol) per week]. The product is quite well differentiated through labelling/product name and is available in a blister pack containing 30 capsules although this pack size is not limited through scheduling. One pack would last 30 weeks.

There is little if any potential for abuse. Lower dose Vitamin D products have been available to consumers for many years at the supermarket and other retail outlets yet consumer awareness of the availability of this once-weekly treatment is low due to prohibition of all forms of advertising.

Delegate's interim decision

The delegate's interim decision is to create a new Appendix H entry for Vitamin D.

The current Schedule 3 entry for vitamin D and proposed Appendix H entry are as follows:

Schedule 3 - Current entry

VITAMIN D for human therapeutic use in preparations containing 175 micrograms or less of vitamin D per recommended single weekly dose except in preparations containing 25 micrograms or less of vitamin D per recommended daily dose.

Appendix H - New Entry

VITAMIN D

The proposed implementation date is 1 June 2017.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: a) the risks and benefits of the use of the substance; b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance; e) the potential for abuse of a substance; and f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the recommendation comprised the following:

The delegate acknowledges the committee's advice.

Access for high-risk consumers to a once-weekly dose of Vitamin D from a pharmacist for effective ongoing supplementation is likely to be beneficial and safe. The compliance benefits, low-risk nature of the product and safeguards inherent in Schedule 3 mean the benefits of advertising the availability of this product exceed any potential risks.

Dosage is as per the Schedule 3 listing [one capsule (7000 IU / 175 micrograms colecalciferol) per week]. The product is quite well differentiated through labelling/product name and is available in a blister pack containing 30 capsules although this pack size is not limited through scheduling. One pack would last 30 weeks.

There is little if any potential for abuse. Lower dose Vitamin D products have been available to consumers for many years at the supermarket and other retail outlets yet consumer awareness of the availability of this once-weekly product is low due to prohibition of all forms of advertising.